Neural injury and degeneration can arise from trauma, disease states, or normal aging and can result in impaired autonomic, sensory, motor, and/or cognitive functions. The peripheral nervous system is capable of considerable regeneration after axonal damage and, thus, offers an opportunity for studying the mechanisms underlying successful regeneration, including the identification of molecules that promote or inhibit regeneration. Our laboratory focuses on changes that occur in the region of the axotomized neuronal cell bodies at some distance from the site of an injury. Our interest is in understanding the mechanisms underlying changes after injury in three populations of cells (neurons, glial cells, and macrophages), the interrelationship of these changes, and their relevance to neural regeneration. Much of our recent research is based on the hypothesis that changes in gene expression in these three cell types are important for promoting regeneration. By microarray analysis, we have identified a large number of genes whose expression changes in sympathetic ganglia after their postganglionic nerve trunks are injured. Many of these genes had not previously been suspected to be part of the response of the nervous system to injury. In addition, some of the changes corroborate earlier findings we made using other techniques. We will examine a subset of these genes with an emphasis on (1) the functional importance of these changes for regeneration, (2) the cell types in which they occur, and (3) the molecular mechanisms underlying their induction. The genes we have chosen for study are all secreted proteins (neuropeptides, cytokines and chemokines) whose expression is substantially increased after axotomy. The central goal of this proposal is to test whether some or all of these proteins are important for successful regeneration. The demonstration of such a role for these molecules should suggest new therapeutic approaches to treating nerve damage [unreadable] [unreadable]